Analysis of the toxicity of gold nano particles on the immune system: effect on dendritic cell functions.

The effect of manufactured gold nanoparticles (NP) on the immune system was analysed through their ability to perturb the functions of dendritic cells (DC), a major actor of both innate and acquired immune responses. For this purpose, DCs were produced in culture from mouse bone marrow progenitors.The analysis of the viability of the cells after their incubation in the presence of gold NP shows that these NP are not cytotoxics even at high concentration. Furthermore, the phenotype of the DC is unchanged after the addition of NP, indicating that there is no activation of the DC. But the analysis of the cells at the intracellular level reveals important amounts of gold NP amassing in endocytic compartments. Furthermore, the secretion of cytokines is significantly modified after such internalisation indicating a potential perturbation of the immune response.

CD2 distinguishes two subsets of human plasmacytoid dendritic cells with distinct phenotype and functions.

Plasmacytoid dendritic cells (pDCs) are key regulators of antiviral immunity. They rapidly secrete IFN-alpha and cross-present viral Ags, thereby launching adaptive immunity. In this study, we show that activated human pDCs inhibit replication of cancer cells and kill them in a contact-dependent fashion. Expression of CD2 distinguishes two pDC subsets with distinct phenotype and function. Both subsets secrete IFN-alpha and express granzyme B and TRAIL. CD2(high) pDCs uniquely express lysozyme and can be found in tonsils and in tumors. Both subsets launch recall T cell responses. However, CD2(high) pDCs secrete higher levels of IL12p40, express higher levels of costimulatory molecule CD80, and are more efficient in triggering proliferation of naive allogeneic T cells. Thus, human blood pDCs are composed of subsets with specific phenotype and functions.

From secretome analysis to immunology: chitosan induces major alterations in the activation of dendritic cells via a TLR4-dependent mechanism.

Dendritic cells are known to be activated by a wide range of microbial products, leading to cytokine production and increased levels of membrane markers such as major histocompatibility complex class II molecules. Such activated dendritic cells possess the capacity to activate naïve T cells. In the present study we demonstrated that immature dendritic cells secrete both the YM1 lectin and lipocalin-2. By testing the ligands of these two proteins, chitosan and siderophores, respectively, we also demonstrated that chitosan, a degradation product of various fungal and protozoal cell walls, induces an activation of dendritic cells at the membrane level, as shown by the up-regulation of membrane proteins such as class II molecules, CD80 and CD86 via a TLR4-dependent mechanism, but is not able to induce cytokine production. This led to the production of activated dendritic cells unable to stimulate T cells. However, costimulation with other microbial products overcame this partial activation and restored the capacity of these activated dendritic cells to stimulate T cells. In addition, successive stimulation with chitosan and then by lipopolysaccharide induced a dose-dependent change in the cytokinic IL-12/IL-10 balance produced by the dendritic cells.

Upon viral exposure, myeloid and plasmacytoid dendritic cells produce 3 waves of distinct chemokines to recruit immune effectors.

Host response to viral infection involves distinct effectors of innate and adaptive immunity, whose mobilization needs to be coordinated to ensure protection. Here we show that influenza virus triggers, in human blood dendritic-cell (DC) subsets (ie, plasmacytoid and myeloid DCs), a coordinated chemokine (CK) secretion program with 3 successive waves. The first one, occurring at early time points (2 to 4 hours), includes CKs potentially attracting effector cells such as neutrophils, cytotoxic T cells, and natural killer (NK) cells (CXCL16, CXCL1, CXCL2, and CXCL3). The second one occurs within 8 to 12 hours and includes CKs attracting effector memory T cells (CXCL8, CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11). The third wave, which occurs after 24 to 48 hours, when DCs have reached the lymphoid organs, includes CCL19, CCL22, and CXCL13, which attract naive T and B lymphocytes. Thus, human blood DC subsets carry a common program of CK production, which allows for a coordinated attraction of the different immune effectors in response to viral infection.